JP2005281268A - Antihistamines solid preparation stable with lapse of time - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technology for obtaining a solid preparation of an antihistaminic agent that is stable with the lapse of time through a simple means. <P>SOLUTION: The solid preparation is capable of substantially keeping the antihistaminic agent and a surfactant from contacting each other within the solid preparation. The preparation that is stable with the lapse of time can be obtained by avoiding the contact between the antihistaminic agent and the surfactant. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a solid preparation of an antihistamine having various effects such as analgesia, antiallergic action and sleep action.

  Drugs having an antihistamine action are used as pharmaceuticals for the purpose of allergic symptoms such as urticaria and hay fever, and various symptoms such as fever due to common cold.

  Histamine is known to cause drowsiness as a typical side effect of antihistamine preparations because it is involved in arousal and excitement in the central nervous system. Recently, diphenhydramine has been used as a highly safe sleep inducer by taking advantage of the side effect of sleepiness.

  As described above, antihistamines have useful effects in various daily lives. In particular, when used as an oral sleep inducer, it is necessary to obtain a rapid effective blood concentration after administration. It becomes. For this reason, how fast the disintegration and dissolution of the preparation is an important factor in the preparation design.

In addition, many antihistamines have many components having an unpleasant taste such as bitter taste as represented by diphenhydramine, mequitazine and the like, and it is substantially difficult to take them as they are. Therefore, the necessity of suppressing bitterness is also necessary from the viewpoint of QOL (Quality of Life). Usually, in order to solve these problems, the granules and tablets are coated with a water-soluble, gastric, enteric, water-insoluble base, etc. There is a way to suppress it. For this reason, diphenhydramine tablets currently available on the market have a fast-dissolving effect due to the bitterness shielding, improved light stability, and quick disintegration by using a light-shielding substance and a water-soluble polymer substance. The formulation is designed (Patent Document 1).

Japanese Patent Laid-Open No. 2003-300872

However, in the case of using a base material for these coatings and matrix type preparations, various problems such as the production of effects, complicated process management, production environment maintenance due to the use of highly toxic organic solvents, etc. have occurred. come. When a gastric soluble base material is used, the gastric base material is not dissolved in elderly people or low gastric acid users, and the expected effect may not be obtained. In the case of an enteric base material, since the base material does not dissolve until the preparation reaches the intestine, it is not suitable for a preparation that expects an immediate effect such as a sleep inducer. Since water-insoluble base materials and matrix preparations are originally base materials that are expected to be durable, they are not suitable for preparations that expect immediate effects. Further, when coating a water-soluble base, there is a problem that the process management becomes complicated because it is necessary to adjust the thickness of the film in the coating.

Further, antihistamines such as diphenhydramine are known to have poor stability and discolor due to light or the like.

As a result of diligent research on the solid preparation of the antihistamine, the inventors of the present invention can obtain a preparation that is stable over time and has sufficient stability as a pharmaceutical product by substantially not bringing the antihistamine into contact with the surfactant. And the present invention was completed.

That is, the present invention
(1) an antihistamine-containing solid preparation that substantially prevents contact with a surfactant,
(2) The preparation according to (1), wherein the surfactant is an anionic or cationic surfactant,
(3) The preparation according to (1) or (2), wherein the antihistamine preparation has an amine group in the chemical structure;
(4) Formulations (1) to (3) which are capsules,
(5) Formulations (1) to (3) characterized in that the raw material of the capsule skin is hydroxypropyl methylcellulose, gelatin or pullulan (6) Capsules are based on hydroxypropylmethylcellulose (1) to ( 5) Formulation (7) Formulation (1) to (6), which further contains another drug,
Is to provide.

The preparation of the present invention can obtain a stable preparation over time by avoiding contact between the antihistamine and the surfactant.

  The pharmaceutical composition of the antihistamine of the present invention should not substantially contact the surfactant and the active ingredient drug.

The antihistamine used in the present invention is not particularly limited as long as it is a drug that can be used as an antihistamine for oral administration. , Doxylamine, tripelenamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, pyrilamine, acribastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, rhodoxanthine, lovatazine methampetine Terfenadine, etc., among these, use alone or in combination of two or more. It may be. Of these, those having an amine group such as diphenhydramine and chlorpheniramine are particularly preferable.

In the present invention, surfactants that should substantially avoid contact with drugs include anionic surfactants, cationic surfactants, and nonionic surfactants. The term “substantially avoiding contact” refers to an aspect in which contact is physically avoided, or the surfactant is not incorporated in an unstable amount in relation to the drug. In particular, it is necessary to avoid contact with an anionic surfactant or a cationic surfactant, and among them, attention should be paid to contact with sodium lauryl sulfate.

As a means for avoiding contact with the surfactant, a small amount is added so that a destabilizing action is not recognized as a method for avoiding contact chemically. The amount in which the destabilizing effect is not observed varies depending on the amount of the surfactant combined with the antihistamine to be used. For example, in the case of diphenhydramine and sodium lauryl sulfate, the amount does not exceed 0.4 parts by weight relative to diphenhydramine. Preferably, it refers to a range not exceeding 0.1 parts by weight, more preferably 0.05 parts by weight, and still more preferably 0.01 parts by weight.

As a method of physically avoiding contact, a surfactant is not blended in the target solid preparation, or even if blended, an active agent drug is separately coated with an inactive agent so that it does not come into contact. . Of these methods of substantially avoiding contact, capsules are preferable from the viewpoint of ease of process control. In the case of capsules, capsule skins that are substantially free of surfactant are used. . The capsule skin is not particularly limited to other base materials and additives as long as the surfactant is not substantially added. Further, the distinction between hard and soft capsule materials is not limited. Preferred examples of the base material include gelatin, hydroxypropylmethylcellulose, starch-modified products such as pullulan, polyvinyl alcohol, acrylic acid, methyl methacrylate, chitin, and chitosan. Hydroxypropyl cellulose and pullulan are particularly preferable.

  In order to improve the moldability of capsules, polyethylene glycol, carrageenan, potassium chloride peanut oil, cetyl alcohol, hardened peanut oil, cetostearyl alcohol, castor oil, stearyl alcohol, hardened castor oil, stearic acid, coconut oil, beeswax, corn oil, dioxide dioxide Silicon, olive oil, polyethylene glycol, hydrogenated vegetable oil, macrogol glycede, silicone oil, poloxalcol, soybean oil, paraffin oil, and the like can also be added as appropriate. In addition, titanium oxide, a dye, or the like can be added as appropriate in order to enhance the light-shielding property and distinguishability of the capsule.

  Furthermore, after filling the capsule with a drug or an additive, a band seal or the like can be applied as appropriate in order to enhance the shielding property, so that the inside of the capsule cannot be removed.

  The method for filling the capsule is not particularly limited, but there are a method in which the capsule is poured directly into the capsule by abrasion, a method in which a capsule is filled with a certain amount of powder and then compressed, a method in which the powder is first compressed, and a capsule is filled. In the case of diphenhydramine, when dissolved in a solvent, there are a method of filling a hard capsule, a method of filling a soft capsule such as a rotary method and a seamless method, and the like.

Another method for preventing the surfactant from contacting is to coat the drug itself. In this case, the composition obtained may be in the form of any oral administration solid preparation such as granules, powders, tablets and the like.

In the antihistamine preparation of the present invention, any component necessary for producing other oral administration solid preparations can be added. Specifically, lubricants, solubilizers, buffers, adsorbents, binders, suspending agents, antioxidants, fillers, pH adjusters, excipients, dispersants, disintegrants, disintegration aids Agents, moisture-proofing agents, preservatives, solvents, solubilizing agents, fluidizing agents and the like can be used.

  In the case of capsules, when the capsule contents are powdered, the antihistamine to be used can be filled as it is, but the additives shown above are added appropriately, mixed and filled, wet granulation, dry granulation There is a method of carrying out granulation or the like to make a powder that is easy to fill with capsules. The method is preferably a method in which additives are appropriately added and mixed, and then filled into capsules. When the capsule content is made liquid, it may be filled after being dissolved in an appropriate solvent.

  As described above, the present invention can obtain a stable solid preparation over time by keeping antihistamine in a substantially non-contact state with a surfactant, particularly when a capsule containing no surfactant is used. Can provide a stable and inexpensive antihistamine preparation.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1
Capsule contents: 50 g of diphenhydramine hydrochloride, 55.8 g of lactose and 2.2 g of hydroxypropylcellulose were mixed by a conventional method. To this mixture, 0.9 g of magnesium stearate was further added and further mixed by a conventional method. The powder thus obtained was used as the capsule contents. 108.9 mg of the obtained powder was fractionated and filled into a capsule made of hydroxypropylmethylcellulose containing no surfactant.

Example 2
The capsule content obtained in Example 1 was filled into gelatin capsules substantially free of surfactant.

Example 3
The capsule content obtained in Example 1 was filled into a pullulan capsule substantially free of surfactant.

Comparative Example 1
108.9 mg of the powder obtained in Example 1 was fractionated and filled into a Japanese Pharmacopoeia gelatin capsule (containing sodium lauryl sulfate).

Test Examples The capsules obtained in Examples 1 to 3 and Comparative Example 1 were left in a thermostat at 50 ° C. for 2 weeks and 3 weeks, and the change in appearance was confirmed. The results are shown in Table 1.

From the results of this test, the formulation of the present invention can obtain a stable formulation over time by avoiding contact with a surfactant.

Since the solid preparation of the present invention can keep the antihistamine stable over time, the preparation obtained by using it can be effectively used for allergic symptoms and sleep induction for insomnia.

Claims (7)

Antihistamine-containing solid preparation that substantially prevents contact with surfactants 2. The preparation according to claim 1, wherein the surfactant is an anionic or cationic surfactant. 3. The preparation according to claim 1, wherein the antihistamine preparation has an amine group in its chemical structure. The preparation according to claims 1 to 3, which is a capsule. 4. The preparation according to claim 1, wherein the raw material for the capsule skin is hydroxypropylmethylcellulose, gelatin, or pullulan. 6. The preparation according to claim 1, wherein the capsule is based on hydroxypropylmethylcellulose. 7. The preparation according to claim 1, further comprising another drug.